Analysis Tools
endocrine/exocrine glands
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• at 8 weeks of age, pancreata show normal gross islet morphology with no change in the number of insulin-positive beta cells, glucagon-positive alpha cells, or total pancreatic cells relative to controls
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• RNA-seq on islets of 8-week-old mice shows downregulation of beta-cell maturation markers, including Ucn3 (urocortin 3), Mafa (MAF bZIP transcription factor A), Slc2a2/Glut2 [solute carrier family 2 (facilitated glucose transporter, member 2], Slc30a8 [solute carrier family 30 (zinc transporter), member 8], Iapp (islet amyloid polypeptide), and Ero1b (endoplasmic reticulum oxidoreductase 1 beta)
• islets of 8-week-old mice show significantly fewer and smaller dense core insulin granules, indicating impaired mature insulin secretory granule formation and beta-cell maturation
• at P1 to 8 weeks of age, islets show complete loss of Mafa, Ucn3, and Slc2a2/Glut2 immunostaining (markers of glucose-responsive beta-cells)
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• pancreatic islets show reduced glucose-stimulated oxygen consumption but no change in maximal respiration (after addition of FCCP)
• islets show significantly reduced mitochondrial membrane potential upon stimulation with glucose, but not following stimulation with the mitochondrial substrate alpha-ketoglutarate
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• at 3 weeks of age, pancreatic beta cell proliferation is significantly increased, as assessed by EdU incorporation into nuclei
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• in perifusion assays, pancreatic islets of 8-week-old mice stimulated with 25 mM glucose show impaired first- and second-phase insulin secretion, with no significant change in total insulin content
• however, islets stimulated with alpha-ketoglutarate or KCl show normal insulin secretion, suggesting a defect upstream of mitochondrial metabolism
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homeostasis/metabolism
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• in perifusion assays, pancreatic islets of 8-week-old mice stimulated with 25 mM glucose show impaired first- and second-phase insulin secretion, with no significant change in total insulin content
• however, islets stimulated with alpha-ketoglutarate or KCl show normal insulin secretion, suggesting a defect upstream of mitochondrial metabolism
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• at 3 and 8 weeks of age, both male and female mice show significantly decreased serum insulin levels at time 0 (fasting) and 10 min after intraperitoneal glucose injection
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• at 3, 6, and 8 weeks of age, intraperitoneal glucose tolerance tests show that both male and female mice are severely glucose intolerant
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cellular
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• pancreatic islets show a significant reduction in mitochondrial count per cell relative to control islets
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• pancreatic islets show a significant increase in average mitochondrial volume relative to control islets
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• RNA-seq on islets of 8-week-old mice shows downregulation of beta-cell maturation markers, including Ucn3 (urocortin 3), Mafa (MAF bZIP transcription factor A), Slc2a2/Glut2 [solute carrier family 2 (facilitated glucose transporter, member 2], Slc30a8 [solute carrier family 30 (zinc transporter), member 8], Iapp (islet amyloid polypeptide), and Ero1b (endoplasmic reticulum oxidoreductase 1 beta)
• islets of 8-week-old mice show significantly fewer and smaller dense core insulin granules, indicating impaired mature insulin secretory granule formation and beta-cell maturation
• at P1 to 8 weeks of age, islets show complete loss of Mafa, Ucn3, and Slc2a2/Glut2 immunostaining (markers of glucose-responsive beta-cells)
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• at 3 weeks of age, pancreatic beta cell proliferation is significantly increased, as assessed by EdU incorporation into nuclei
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• dispersed pancreatic islets from 8-week-old mice show significantly reduced glucose uptake, as measured by 2-NBDG (a glucose analog), relative to control islets
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• pancreatic islets appear to show altered mitochondrial fission/fusion dynamics, likely due to beta cell immaturity
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growth/size/body
| N |
• 8-week-old mice (male and female combined) exhibit normal body weight relative to age-matched controls
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